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Bahan Ajar 4 Fenilketonuria

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  BAHAN AJAR IV Phenylketonurias (Phenylalanine Hydroxylase Deficiency)   Nama Mata Kuliah/Bobot SKS : Sistem Neuropsikiatri / 8 SKS Standar Kompetensi : area kompetensi 5: landasan ilmiah kedokteran Kompetensi Dasar : menerapkan ilmu kedokteran klinik pada sistem neuropsikiatri Indikator : menegakkan diagnosis dan melakukan penatalaksanaan awal sebelum dirujuk sebagai kasus emergensi Level Kompetensi : 1  Alokasi Waktu : 1 x 50 menit 1. Tujuan Instruksional Umum (TIU) : Mampu mengenali dan mendiagnosis penyakit-penyakit genetik dan kongenital serta melakukan penangan sesuai dengan tingkat kompetensi yang ditentukan, dan melakukan rujukan bila perlu. 2. Tujuan Instruksional Khusus (TIK) : a. Mampu menyebutkan patogenesis terjadinya Fenilketonuria   b. Mampu melakukan promosi kesehatan dan pencegahan Fenilketonuria   Isi Materi;  BAB I PENDAHULUAN Phenylketonuria (PKU) is an inborn error of metabolism involving impaired metabolism of the amino acid phenylalanine. Phenylketonuria is caused by absent or virtually absent phenylalanine hydroxylase (PAH) enzyme activity.   Phenylketonurias is the most frequent of the aminoacidurias disease and occur of the late infantile and early childhood period. Since its discovery by Følling in 1934, it has remained the classic example of an aminoaciduria and illustrates three principles of medical genetics: first, it is inherited as an autosomal recessive trait; second, it exemplifies Garrod’s cardinal principle of gene action, in which genetic factors specify chemical reactions as well as biochemical individuality; third, PKU is expressed only in an environment that contains an abundance of L-phenylalanine. Thus, as pred icted by Galton, the ultimate phenotype is a product of “nature and nurture”.    Patophysiology, Signs, and Symptoms  At birth, the typical PKU infant is believed to have a normal nervous system. The disease appears later, only after long exposure of the nervous system to phenylalanine (PA), because the homozygous infant lacks the means of protecting the nervous system. However, if the mother is homozygous with high PA levels in the blood during pregnancy, the CNS is damaged in utero and the heterozygous infant is mentally defective from birth. The damage done to the brain if PKU is untreated during the first months of life is not reversible. It is critical to control the diet of infants with PKU very carefully so that the brain has an opportunity to develop normally. Affected children who are detected at birth and treated are much less likely to develop neurological problems or have seizures and intellectual disability (though such clinical disorders are still possible.) In the classic form of PKU, the impairment of psychomotor development   can usually be recognized in the latter part of    the first year, when expected performance lags. By 5 to 6   years in an untreated child, when the IQ can be estimated,   it is usually less than 20, occasionally 20 to 50, and exceptionally   above 50. Hyperactivity  ,   aggressivity,   self-injurious behavior  —including severe injury to the eyes, clumsy gait, fine tremor of the hands, poor coordination, odd posturings, repetitious digital mannerisms  and other so-called rhythmias, and slight corticospinal tract signs stand out as the main clinical manifestations. Athetosis, dystonia, and frank cerebellar ataxia have been described but must be rare. Also, seizures occur in a small minority of severely affected patients (abnormal EEG finding), taking the form at first of flexor spasms and later of absence and grand mal attacks. The majority of PKU patients are blue-eyed and fair in skin and hair color, and their skin is rough and dry and subject to eczema. A musty or mousy body odor (because of phenylacetic acid  excretion) can often be detected. Two-thirds are slightly microcephalic. The fundi are normal, and there is no visceral enlargement or skeletal abnormality. In untreated phenylketonuria (PKU), deficiency of phenylalanine hydroxylase (PAH) results in elevated blood phenylalanine (Phe) concentrations and severe mental retardation. There are some people living in the community with asymptomatic PKU and normal intelligence. Adult onset PKU is rare and if found, they developed a progressive spastic paraparesis, some with mild dementia. The phenylalanine levels were at values that reflect total or partial enzyme deficiency.  Figure 1. Metabolism of phenylalanin Phenylalanine (phe) metabolism in phenylketonuria (PKU). As indicated by the “X”, PKU results from mutations (over 800 have been identified) that affect the hepatic phe hydroxylase (PAH) enzyme needed for the hydroxylation of the indispensable amino acid phe to tyrosine. PKU may also result from mutations in the recycling of the essential PAH cofactor tetrahydrobiopterin. Due to these mutations  which reduce the conversion of phe to tyrosine, phe accumulates in  blood and is transaminated and decarboxylated into many compounds  which appear in blood and urine; three of the compounds which are measured clinically are shown. Tyrosine, a precursor for multiple  biological products, becomes an indispensable AA and must be provided by the diet for those with PKU. Under physiological conditions PAH catalyzes about 75% of the phe input from the diet and protein catabolism.  
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